The present invention relates to oxygen-17 nuclear magnetic resonance spectroscopy and imaging apparatus and methods in the living human, including the determination of blood flow and oxygen metabolism rates.
Various isotopes have been considered for use in connection with nuclear magnetic resonance (NMR) spectroscopy and imaging systems, which are in widespread use. Most NMR systems in use today are based on the hydrogen-1 isotope because that isotope can be easily detected in humans for a number of reasons, including the fact that hydrogen-1 has a relatively large nuclear magnetic moment and the fact that its concentration in humans is relatively large. Those two factors allow conventional NMR systems to generate NMR signals having a relatively large signal-to-noise (S/N) ratio. The S/N ratio is a measure of how easily an isotope can be detected in NMR.
Other isotopes have been considered for use in NMR. Research has been conducted in connection with oxygen-17 NMR, mainly in connection with small laboratory animals. It has been generally acknowledged that oxygen-17 NMR spectroscopy and imaging are difficult for a number of reasons. First, oxygen-17 has a relatively weak magnetic moment, which is approximately 7.4 times weaker than the magnetic moment of hydrogen-1, which is commonly imaged by conventional NMR systems. Hydrogen-1 imaging is commonly referred to as "proton" imaging. The weaker magnetic moment of oxygen-17 results in a smaller S/N ratio than that which can be accomplished with hydrogen-1.
Another obstacle to oxygen-17 NMR is the very low concentration, or natural abundance, of oxygen-17, which fact further reduces the S/N ratio which could be achieved in oxygen-17 NMR. The natural abundance of the oxygen-17 isotope in air is only 0.037%. Due to inhalation of air containing oxygen-17, the natural abundance of oxygen-17 in the water of tissues in animals and humans is also 0.037%.
These obstacles to oxygen-17 NMR have been recognized by those working in the field. For example, in U.S. Pat. No. 4,984,574 issued in 1991, Goldberg, et al. state: "It might, accordingly, be thought that existing NMR methods could be applied to measure the oxygen content of living human fetuses. Such a direct application, however, seems infeasible for reasons including the following: First, naturally occurring oxygen consists mainly of .sup.16 O, whose nucleus possesses no magnetic moment (hence has gyromagnetic ratio zero) and so cannot be studied by NMR. The natural abundance of .sup.17 O, which does possess a magnetic moment, is only 0.37% (sic, 0.037%) and its intrinsic sensitivity is approximately 1.08.times.10.sup.-5 times that of .sup.1 H. As a result, the NMR signal from oxygen within a natural sample or living creature is only some four billionths as strong as the signal from an equal concentration of hydrogen nuclei within it, effectively ruling out any chance of detection by available methods."
Instead of utilizing oxygen-17 NMR, oxygen-17 has been used as a contrast agent in hydrogen-1 NMR. For example, in Oxygen-17 Compounds as Potential NMR T.sub.2 Contrast Agents: Enrichment Effects of H.sub.2.sup.17 O on Protein Solutions and Living Tissues, published in 1987, Hopkins, et al. disclose that the isotopic enrichment of solutions, living tissues, and organisms with oxygen-17 in the form of H.sub.2.sup.17 O shortens their proton (hydrogen-1) NMR transverse relaxation times (T.sub.2) and suggest that oxygen-17 would therefore be useful as a contrast agent. In particular, Hopkins, et al. state: "Since changes in proton T.sub.2 can alter image intensity, localized variation in H.sub.2.sup.17 O concentrations could be directly visualized as well as monitored in samples with the usual proton equipment and T.sub.2 procedures."
Oxygen-17 NMR research has been performed by Professor Gheorghe D. Mateescu and others at the Case Western Reserve University in Ohio. In an abstract entitled Oxygen-17 Magnetic Resonance Imaging from the Sixth Annual Meeting of the Society of Magnetic Resonance in Medicine in 1987, Mateescu, et al. acknowledged the difficulties in oxygen-17 imaging: "Water is the primary signal source in Magnetic Resonance Imaging. So far, proton detection has been exclusively used because of its high sensitivity, while the O-17 nucleus has generally been considered impractical for MRI, owing to its `unfavorable` properties: very low natural abundance, low detection sensitivity, and considerable quadrupolar broadening." The authors went on to state that some of the "drawbacks" of oxygen-17 imaging could be turned into "advantages" and further stated: "The O-17 projection reconstruction of a T-shaped phantom shown in FIG. 1 compares favorably with the proton image of a similar phantom described in a review by Andrew..sup.3 Although 1000 times less sensitive, the O-17 measurement in natural abundance takes only .about.10 times longer than the proton measurement. This is clue to its much faster (quadrupolar) relaxation time which allows many more scans per unit time."
In Combined .sup.17 O/.sup.1 H Magnetic Resonance Microscopy in Plants, Animals and Materials: Present Status and Potential published in 1989, Mateescu, et al., in a section entitled "Basic Principles of Magnetic Resonance Imaging," state: "Since the measurement is always made some time after pulse excitation and, in order to build sufficient signal-to-noise it is necessary to accumulate the signals of repetitive scans, the image intensity depends on both the T.sub.2 and T.sub.1 properties of the specimen. This makes it possible to obtain T.sub.1 or T.sub.2 weighted images by selecting an imaging sequence with appropriately ordered and timed rf and gradient pulses." In connection with the magnetic resonance properties of oxygen-17, Mateescu, et al. stated that the fast quadrupolar relaxation time of oxygen-17 allows pulsing rates at least 20 times faster without signal loss.
In an abstract entitled Oxygen-17 MRI and MRS of the Brain, the Heart and Coronary Arteries from the Eighth Annual Meeting of the Society of Magnetic Resonance in Medicine in 1989, Mateescu, et al. illustrated in vitro oxygen-17 images of a human heart and coronary arteries. The images were of an excised human heart into which 20% oxygen-17 water was injected after ligation of the three ends of the coronary segment.
It has been suggested that oxygen-17 NMR spectroscopy and imaging might be used in humans. In In Vivo Measurement of Cerebral Oxygen Consumption and Blood Flow Using .sup.17 O Magnetic Resonance Imaging, published in 1991 by Pekar, et al., the authors, who include the inventor of the present invention, state that "In summary, .sup.17 O NMR techniques have been used to measure cerebral blood flow and oxygen consumption in a 0.8-ml voxel in the cat brain. The technique has the potential to image cerebral blood flow and oxygen consumption in humans."
Despite the above suggestions that oxygen-17 imaging might be successfully employed in humans, to the inventor's knowledge there has not been any report of successful oxygen-17 imaging in living human beings. Although the above abstracts and papers suggest imaging could be accomplished in humans, the actual experiments were generally carried out with laboratory animals or inanimate objects, e.g. an excised in vitro human heart. The use of laboratory animals allows relatively large magnetic fields, e.g. 9.4 Tesla device in the 1989 abstract of Mateescu, et al. referenced above, which are unsuitable for use on living human beings. The maximum magnetic field approved for use with living humans by the U.S. Food and Drug Administration is 2 Tesla. The use of a larger magnetic field for laboratory animals and inanimate objects results in a larger S/N ratio which allows images to be generated more easily.
Also, many of the oxygen-17 images reported above were generated based on the injection of relatively large amounts of oxygen-17 enriched water, the result of which increased the oxygen-17 concentration greatly above the 0.037 % natural abundance level. Although high-concentration oxygen-17 injections increase the S/N ratio, such invasive methods of increasing the oxygen-17 concentration (which often resulted in the death of the laboratory animals) are inappropriate for use in living humans.
A prior art NMR imager which has been in widespread use for more than a year is the Signa 1.5 Tesla imager commercially available from General Electric. The GE imager has a superconducting magnet for generating a static magnetic field of 1.5 Tesla. The imager has various modes of operation including, for example, a multi-planar, gradient recalled (MPGR) mode.
In the MPGR mode, a resonant magnetic field and gradient magnetic fields are generated. The resonant magnetic field, which induces resonance of hydrogen-1 constituents, is generated via a number of Hermitian pulses transmitted at a repetition rate TR. Although the RF frequency of the Hermitian pulses is variable between upper and lower limits as selected by the operator, the GE imager is typically used to cause magnetic resonance of hydrogen-1 constituents. Because the lower frequency limit is too high, the GE imager is incapable of generating a Larmor frequency that would cause magnetic resonance of oxygen-17 constituents.
In the GE imager, the gradient magnetic fields are generated by a number of G.sub.x, G.sub.y, G.sub.z pulses. The spacing of the G.sub.x pulse with respect to the Hermitian pulse is determined by an echo time TE. In the GE imager, both the echo time TE and the repetition time TR are selectable by the user within limits. The lower and upper limits for TE are 9 and 600 milliseconds (ms), respectively, and the upper and lower limits for TR are 34 and 6,000 ms, respectively. The GE imager also performs sample averaging of a plurality of hydrogen-1 NMR signals for a particular area of a human body. The number of samples which are averaged, which is referred m as "NEX, " is selectable by the operator of the imager.
The GE imager is incapable of generating oxygen-17 images for at least the following reasons. The GE imager is incapable of transmitting an RF signal at a Larmor frequency for oxygen-17 constituents; the lower limits of the TE and TR times are too high to facilitate the generation of oxygen-17 images; and the hardware of the GE imager does not provide sufficient low-noise amplification of the NMR signals to facilitate the generation of oxygen-17 images.
The accurate determination of the oxygen metabolism rate in various portions of a live human being is important for numerous clinical applications. For example, the cerebral oxygen metabolism rate is important for clinical applications include assessing dementia, treating brain tumors, detecting cerebral ischemia (oxygen-deficiency), and understanding neurobehavioral disorders. The oxygen metabolism rates in other organs, such as the heart or lungs, is important for other clinical applications.
One conventional manner of determining the rate of oxygen consumption in a live human being is positron emission tomography (PET). Such systems operate by detecting radioactive oxygen isotopes, such as oxygen-15. PET systems have a number of significant disadvantages. Because PET systems rely on radioactive isotopes, they require cyclotrons, which are expensive and difficult to operate. Because the half-life of the radioactive isotope is typically short, e.g. 124 seconds of oxygen-15, the cyclotron must be situated relatively near the PET system and provide an on-line supply of oxygen-15. As a result, PET systems are typically very expensive, on the order of $7 million. The cost of a single PET determination is also expensive, being on the order of $10,000. A further disadvantage of the use of radioactive isotopes by PET systems is that PET determinations are usually not repeated more than two to three times in adults and are rarely used for children and infants. PET systems also require catheterization.
Another significant disadvantage is the methodology on which PET systems are based. The consumption of oxygen results from metabolism of glucose in accordance with the following equation: EQU glucose+.sup.15 O.sub.2 .fwdarw.CO.sub.2 +H.sub.2.sup.15 O
The fact that radioactive oxygen-15 is present in both the substrate (.sup.15 O labelled oxyhemoglobin) and the oxygen-15 water product, and the fact that the PET system detects both the radioactive oxyhemoglobin and radioactive oxygen-15 water, make it difficult to distinguish between the oxyhemoglobin substrate and the water product as well as the reflow of oxygen-15 water and complicates and introduces errors in the calculation of the oxygen consumption rate. Although the PET system utilizes semi-empirical equations to overcome that difficulty, the use of such equations casts doubt on the accuracy of the PET method to determine the rate of oxygen consumption. For example, it has been found that upon light stimulation, the metabolism of glucose in an area of tissue increased while the rate of oxygen consumption in the tissue area decreased, which result is doubtful since glucose metabolism and oxygen consumption are directly, not inversely, related.
Mateescu, et al. have done NMR research in connection with inhalation of oxygen-17 by animals. In an abstract entitled Oxygen-17 Magnetic Resonance: In vivo Detection of Nascent Mitochondria Water in Animals Breathing .sup.17 O.sub.2 Enriched Air from the 10th Annual Meeting of the Society of Magnetic Resonance in Medicine, Mateescu, et al. tracked the quantity of H.sub.2.sup.17 O in the head of a mouse. Mateescu, et al. stated that: "Our results show that good quantitation can be obtained from volumes smaller than 1 cm.sup.3. This indicates that a good resolution should be obtained with larger animals and humans."
In the above abstract, although Mateescu, et al. disclose tracking the amount of H.sub.2.sup.17 O in the mouse head, they did not determine the true rate of oxygen consumption or the rate of blood flow in the mouse head because they failed to account for the appearance of H.sub.2.sup.17 O due to reflow effects resulting from the recirculation of H.sub.2.sup.17 O-enriched blood. It has been recognized that the amount of H.sub.2.sup.17 O present in a portion of tissue is due to two components: 1) the production of H.sub.2.sup.17 O in the tissue due to metabolism; and 2) the change in H.sub.2.sup.17 O in the tissue due to H.sub.2.sup.17 O-enriched blood flow into and out of the tissue. Thus, Mateescu, et al. failed to account for the second component above.
That the amount of H.sub.2.sup.17 O present in a portion of tissue is due to the above two components is described in In Vivo Measurement of Cerebral Oxygen Consumption and Blood Flow Using .sup.17 O Magnetic Resonance Imaging, published in 1991 by Pekar, et al., including the inventor. That paper describes a method of in vivo measurement of the rate of cerebral oxygen consumption and blood flow in a cat via oxygen-17 NMR via bolus injections of oxygen-17 enriched water and inhalation of oxygen-17 enriched air. The increase of H.sub.2.sup.17 O in the cat brain due to reflow and the increase of H.sub.2.sup.17 O due to metabolism are shown in the graph of FIG. 3 of the paper.
There are several other methods used for the determination of localized blood flow, such as the magnitude of blood flow in the brain. One widely used method of determining the rate of localized blood flow in the human is the single photon emission computed tomography (SPECT) system. However, SPECT systems have a number of significant disadvantages in that they use radioactive isotopes and they do not generate quantitative data regarding blood flow, but only generate data indicative of the relative rate of blood flow in different portions of the body.